Repairing folding-defective \u3b1-sarcoglycan mutants by CFTR correctors, a potential therapy for Limb Girdle Muscular Dystrophy 2D

Limb Girdle Muscular Dystrophy type 2D (LGMD2D) is a rare autosomal-recessive disease, affecting striated muscle, due to mutation of SGCA, the gene coding for \u3b1-sarcoglycan. Nowadays more than 50 different SGCA missense mutations have been reported. They are supposed to impact folding and trafficking of \u3b1-sarcoglycan because the defective polypeptide, although potentially functional, is recognized and disposed of by the quality control of the cell. The secondary reduction of \u3b1-sarcoglycan partners, \u3b2-, \u3b3- and \u3b4-sarcoglycan, disrupts a key membrane complex that, associated to dystrophin, contributes to assure sarcolemma stability during muscle contraction. The complex deficiency is responsible for muscle wasting and the development of a severe form of dystrophy.Here, we show that the application of small molecules developed to rescue \u394F508-CFTR trafficking, and known as CFTR correctors, also improved the maturation of several \u3b1-sarcoglycan mutants that were consequently rescued at the plasma membrane. Remarkably, in myotubes from a patient with LGMD2D, treatment with CFTR correctors induced the proper re-localization of the whole sarcoglycan complex, with a consequent reduction of sarcolemma fragility. Although the mechanism of action of CFTR correctors on defective \u3b1-sarcoglycan needs further investigation, this is the first report showing a quantitative and functional recovery of the sarcoglycan-complex in human pathologic samples, upon small molecule treatment. It represents the proof of principle of a pharmacological strategy that acts on the sarcoglycan maturation process and we believe it has a great potential to develop as a cure for most of the patients with LGMD2D

Combination of immunosuppressive treatment and antimicrobial drugs: effect on colonic microflora of rat.

Combination of immunosuppressive treatment and antimicrobial drugs: effects on colonic microflora of ra

Sarcoglycanopathies, therapeutic approaches based on small molecules

Sarcoglycanopathies are rare autosomal recessive diseases affecting striated muscle, sharing a similar phenotype. The pathology is due to defects in four genes, SGCA, SGCB, SGCD and SGCG coding for \u3b1-, \u3b2-, \u3b4- and \u3b3-sarcoglycan (SG), respectively. SGs form a key tetramer that, embedded in the major dystrophin associated protein complex, concurs to the structural stability of the sarcolemma during muscle contraction. When a mutation is present in one of the SG-genes, the entire SG-complex disappears or is strongly reduced and a progressive muscle degeneration leads to the development of the disease. Most of the SG-gene defects are missense mutations leading to the production of folding-defective protein, recognized and rapidly removed by the quality control system of the cells. At present, no effective treatment is available for sarcoglycanopathy, however, the knowledge of the pathogenic mechanism allowed us to design a novel pharmacological strategy. Indeed, we proved that by using small molecules able to inhibit some components of the degradative pathway, the mutated SG and the SG-complex can be recovered at the plasma membrane. These results have been collected in cell models and in primary myotubes from an \u3b1-sarcoglycanopathy patient. As a second pharmacological approach, we have also tested compounds known as CFTR-correctors supposed acting on the folding process of SGs. The results obtained are extremely promising, as some of these small molecules are effective in recovering the SG-complex in cell models and in myotubes form both \u3b1- and \u3b2-sarcoglycanopathy patients. Importantly, although containing a defective member, the rescued SG-complex is functional as the strength of the myotube sarcolemma improved, upon treatment with CFTR-correctors. Our lab is currently focusing on the development and characterization of novel mouse and zebrafish models of the disease, suitable for testing effectiveness of the small molecules in vivo. Experiments aiming at understanding the mechanism of action of CFTR-correctors in sarcoglycanopathy are also ongoing

Procedura di rialzo del seno monofasica verso bifasica: risultati ad 1 anno dal carico di uno studio controllato randomizzato multicentrico.

OBIETTIVO: Confrontare l\u2019efficacia della procedura di rialzo del seno mascellare laterale monofasica verso quella bifasica. MATERIALI E METODI: Sono stati inclusi 60 pazienti parzialmente edentuli che necessitavano da 1 a 3 impianti e con un\u2019altezza ossea residua di 1- 3 mm e uno spessore di almeno 5 mm al di sotto del seno mascellare, misurata su tomografie computerizzate. I pazienti sono stati randomizzati secondo un disegno di studio a gruppi paralleli in 2 gruppi per essere sottoposti a procedura di rialzo del seno in un unico intervento (monofasica) mediante apertura di una finestra laterale e contestuale posizionamento degli impianti oppure ad una procedura di rialzo del seno in 2 interventi (bifasica) con posizionamento degli impianti a distanza di 4 mesi dal rialzo di seno con sostituto d\u2019osso. Gli interventi sono stati eseguiti in 3 centri diversi. Gli impianti sono rimasti sommersi per 4 mesi e in seguito caricati con protesi provvisorie rinforzate, che sono state sostituite dopo 4 mesi con protesi definitive. I parametri di successo, valutati da valutatori in cieco sono stati: fallimenti delle procedure di aumento, fallimenti protesici e fallimenti implantari; complicazioni; e variazioni dei livelli ossei marginali peri-implantari. I pazienti sono stati seguiti fino ad 1 anno dal carico. Sono qui riportati solo i dati relativi agli impianti posizionati in un\u2019altezza ossea subantrale fra 1 e 3 mm. RISULTATI: Nel gruppo della procedura monofasica ci sono stati 2 drop-out verso nessuno per il secondo gruppo. Non c\u2019\ue8 stato nessun fallimento delle procedure di rialzo nel gruppo monofasico verso un fallimento nel gruppo bifasico, ma la differenza non \ue8 stata statisticamente significativa (P = 1,00). Ci sono stati 2 fallimenti protesici (o casi in cui non \ue8 stato possibile posizionare le protesi nel tempo previsto) nel gruppo monofasico e uno nel gruppo bifasico, ma la differenza non \ue8 stata statisticamente significativa (P = 0,51). Sono falliti 3 impianti in 3 pazienti nel gruppo monofasico verso 1 nel gruppo a bifasico, ma la differenza non \ue8 stata statisticamente significativa (P = 0,28). Si sono verificate 2 complicazioni nel gruppo monofasico e 1 nel gruppo bifasico, ma la differenza non \ue8 stata statisticamente significativa (P=0,61). Ad 1 anno dal carico, i pazienti trattati con procedura monofasica hanno perso di media -1,01 mm (DS: 0,56) di osso peri-implantare verso -0,93 mm per i siti del gruppo bifasico (DS: 0,40). Non sono state riscontrate differenze statisticamente significative a livello di variazioni dei livelli ossei tra i 2 gruppi a distanza di 1 anno dal carico (-0,08 mm IC 95%: da -0,33 a 0,18, P = 0,56). CONCLUSIONI: Non \ue8 stata osservata nessuna differenza staticamente significativa tra le 2 procedure di rialzo del seno. Tuttavia, il presente studio potrebbe suggerire che in pazienti con un\u2019altezza ossea residua compresa tra 1 e 3 mm al di sotto del seno mascellare, il rischio di fallimento implantare \ue8 leggermente superiore per la procedura monofasica

Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT.

OBJECTIVES: To establish the level of observer variation for the current ATS/ERS/JRS/ALAT criteria for a diagnosis of usual interstitial pneumonia (UIP) on CT among a large group of thoracic radiologists of varying levels of experience. MATERIALS AND METHODS: 112 observers (96 of whom were thoracic radiologists) categorised CTs of 150 consecutive patients with fibrotic lung disease using the ATS/ERS/JRS/ALAT CT criteria for a UIP pattern (3 categories--UIP, possibly UIP and inconsistent with UIP). The presence of honeycombing, traction bronchiectasis and emphysema was also scored using a 3-point scale (definitely present, possibly present, absent). Observer agreement for the UIP categorisation and for the 3 CT patterns in the entAUe observer group and in subgroups stratified by observer experience, were evaluated. RESULTS: Interobserver agreement across the diagnosis category scores among the 112 observers was moderate, ranging from 0.48 (IQR 0.18) for general radiologists to 0.52 (IQR 0.20) for thoracic radiologists of 10-20 years' experience. A binary score for UIP versus possible or inconsistent with UIP was examined. Observer agreement for this binary score was only moderate. No significant differences in agreement levels were identified when the CTs were stratified according to multidisciplinary team (MDT) diagnosis or patient age or when observers were categorised according to experience. Observer agreement for each of honeycombing, traction bronchiectasis and emphysema were 0.59+/-0.12, 0.42+/-0.15 and 0.43+/-0.18, respectively. CONCLUSIONS: Interobserver agreement for the current ATS/ERS/JRS/ALAT CT criteria for UIP is only moderate among thoracic radiologists, AUrespective of theAU experience, and did not vary with patient age or the MDT diagnosis

Age level vs grade level for the diagnosis of ADHD and neurodevelopmental disorders

A number of worldwide studies have demonstrated that children born later in the school year are more likely to receive an ADHD diagnosis than their same school-year peers. There is, however, variation in findings between countries. We aimed to confirm whether relative age is associated with ADHD diagnosis, with or without comorbidities, and to investigate whether relative age is associated with ADHD type and severity, and if this age relationship is in common with other neurodevelopmental disorder. We used the Lombardy Region\u2019s ADHD registry. Data on children aged 6\ua0years and older from September 1, 2011 to December 31, 2017 were considered. We calculated incidence ratios to assess the inter-relations between relative age within the school year, using age at diagnosis of ADHD or of other psychiatric disorder, year of diagnosis, and total number of children born in Lombardy during the corresponding timeframe. Data on ADHD type, severity of diagnosed disorder clinical global impressions\u2013severity scale, and repetition of a school-grade were also considered. 4081 children, 2856 of whom with ADHD, were identified. We confirmed that the cumulative incidence of ADHD diagnosis was greatest for younger children, in particular for boys, for whom the prevalence is greater. The relative age effect was not accounted for by ADHD comorbid disorders, ADHD of combined type or severity. The relative age effect was also observed for children with other neurodevelopmental disorders (without ADHD), with a similar profile as ADHD children: the incidence ratio was 1.78 (95% CI 1.07\u20132.97; p < 0.0247) for boys diagnosed before age ten. The findings have a potential implication for diagnostic and therapeutic practice, educational advice, and policies, besides to better plan and organize service systems and appropriately inform parents, children, and citizens

Differences between centers in functional outcome of patients with ADHD after 1 year from the time of diagnosis

Although the pharmacological therapy of ADHD has been widely studied, little has been done to compare the different therapeutic approaches (e.g., drug therapy vs. psychological treatments) and even less has been done to compare the outcome of the therapy between centers. This multicenter observational study aims to assess between-center variation in functional outcome of ADHD patients one year after the diagnosis, according to the treatment received. We used the Regional ADHD Registry data on 1429 patients enrolled in 16 ADHD centers in the 2011-2022 period. To evaluate the effectiveness of the therapy we used a generalized linear mixed model with the center as the random effect, including patient condition at diagnosis and center characteristics, weighting by the inverse of the propensity score of the treatment received by the patient. Between-center variation was expressed as the relative difference in odds-ratios between the observed and the expected number of patients whose condition improved, using the Clinical Global Impressions-Improvement Scale (CGI-I), and the relative 95% CI. Patients who received combined treatment were significantly more likely to improve compared to other treatment groups (65.5% vs 54.4% for methylphenidate alone, 53.4% for psychological treatment alone, or 40.5% for no therapy). Adjusted for patients and center characteristics, the log-odds ratio ranged from 0.85 (0.29-1.55 95% CI) to -0.64 (-1.17-0.18 95% CI). The mean expected probability of improvement after one year of therapy for an average patient with ADHD for each center was 47.7% in a center at the 25th percentile and 61.2% in a center at the 75th percentile of the outcome distribution after adjustments. The wide between-center variation in patient functional improvement one year after the diagnosis of ADHD could be largely explained by center-specific therapeutic approaches or attitudes. More careful and stringent work is needed to reduce differences in responses between centers, as could formal and periodic audit programs within and between centers